Why Genetics Is Important in MDS and How It Affects Prognosis

Why is genetics important in MDS and how does it affect prognosis?

I think it probably is best to start with really what MDS is, you know.

And so the way that I think about myelodysplastic syndrome, Mylo, meaning marrow dysplastic meaning dysfunction, is a dysfunctional marrow. So what ends up happening is normally a molecular mutation occurs and it leads to dysfunction in the cell lines.

You know we have white blood cells. White blood cells fight infections. We have red blood cells. Red blood cells provide oxygen to our body. And we have platelets. Platelets help with clotting.

And so in myelodysplastic syndrome we get a genetic change that occurs that then causes dysfunction in one or all three of those cell lines.

it's not like a genetic change, when you think of, you know, something that you would pass down from generation to generation, this is something that you actually acquire with age. So as you get older, you're more likely to acquire a genetic change in your blood.

Actually, in all patients above 70, if you test normal individuals, about 10% of them have an MDS related genetic change.

But then there's there's normally sort of a second hit, whether it's environmental or, you know, bad luck in some cases that leads to additional genetic changes that ultimately moves forward with dysfunction of the marrow.

And so MDS patients, when they present, they present with a lot of times low red blood cells because a dysfunction in the red blood cells. But they can also present with low white blood cells, low platelets because of dysfunction in those areas.

And when you have this dysfunction the cells don't work correctly. They get destroyed quickly. And it leads to low blood counts and complications related to that.

So I think with genetics, that really is it's the driver of the disease. It allows us to help with, the diagnosis of myelodysplastic syndrome in certain cases. It helps us to understand the prognosis of myelodysplastic syndrome.

So when we talk about genetics and MDS, what we're really generally referring to are genomics. And what I mean by that is these mutations that we're looking for in association with MDS are not mutations that an individual is born with.

There are mutations that are acquired over the course of an individual's lifetime, and they're generally only found in the bone marrow and blood cells. If you were to swab a patient's cheek, we would not find most of these mutations that matter in MDS.

They're important because they tell us about how a patient will do, how they help us to determine sort of disease severity of MDS and what a patient's course is likely to be over the next several years.

Genetics especially nowadays is very important, particularly for MDS as it is nowadays, by default, genetic mutations are tested.

So if you get a bone marrow biopsy for MDS and most academics center, genetic mutations are tested, genetic profiles are important in giving patients prognosis.

So by looking at particular set of mutations, we can make an educated guess in how long patients can live without relapse, how well they respond to chemotherapy or how poorly they respond to chemotherapy.

in addition, there are a couple mutations that we have targeted agents for. So if you if a patient happens to have one of those mutations, we can use, specific set of therapy to target those, mutations.

It's a very important information to have to choose the right therapy to tell the patient how, what to expect. Even tell them in a general sense how well you will do in the future.

And in some patients, we can also, risk categorize. What's the risk level of having an inherited mutation?

So most of the mutations are acquired. It's not inherited. It's not, something that you were born with. Something that you will not inherit to your children. That takes about 90% of the cases.

It's a newly developing field in about 10 to 20% of the cases. Now, we know that, MDS might have been caused by inherited mutation, inherited gene changes. And that can, be carried to your offspring.

So when we think a patient is a high risk for that type of mutations, then we also screen them for inherited, possibly inherited genes as well.

And, those type of patients are, patients who were diagnosed with either leukemia or MDS at a younger age, for example, less than around 50 years of age, or, those patients who have multiple family members with various cancer, or those patients who have more than one cancer.

So if you have MDS or leukemia, and have another type of cancer, then then we start thinking about screening them for, potentially, some mutations that they were born with that they were inherited with.

Regardless, gene testing, gene mutations and testing genetic profile is extremely important for MDS.

Do a patient's genetics help determine their treatment protocol?

Now, we have a risk calculator that actually incorporates genetics and the IPSS-M. And so that's something that we use as clinicians to really look at clinical factors as well as genetic factors, to be able to better predict who's going to do well, who might need potentially a bone marrow transplant, who might be able to just get supportive care, and who might we might be able to observe and not do anything for those patients.

So there are two major prognostic scoring systems that I would like to talk about.

One of them is the IPSS-R or our international prognostic scoring system, the revised version. And the other one is the IPSS-M, which is the molecular international prognostic scoring system.

Both of these scoring systems integrate sort of genetic and clinical data to come up with a prognostic score for patients. And that can inform sort of disease severity. It can inform risk of transformation to acute myeloid leukemia. And it can inform overall survival.

So the IPSS are really focuses on cytogenetics. These big chromosomal changes in concert with clinical parameters. Excuse me.

And then the IPSS-M not only does this cytogenetics and the clinical but also incorporates these smaller molecular changes such as mutations in individual genes.

So by using these, scoring systems, it can give you an idea, of who might be most likely to progress with or transform to acute myeloid leukemia or who might not respond to therapies, that are sort of standard of care.